Abstract Hermansky-Pudlak Syndrome (HPS) is a group of inherited autosomal recessive disorders caused by genetic mutations that alter the trafficking of lysosomal-related organelles/vesicles. In patients with HPS-1 and HPS-4 subtypes, pulmonary fibrosis develops in the fourth or fifth decade of life, and is the major cause of morbidity and mortality. Although the genetic alterations that underlie HPS are well defined, the mechanisms that mediate the development of pulmonary fibrosis have not been elucidated. As a result, therapeutic targets that can be manipulated to control the development of pulmonary fibrosis in HPS have not been described. Chitinase 3-like 1(CHI3L1) is the prototypic chitinase-like protein. Studies from our laboratory and others demonstrated that circulating levels of CHI3L1 are 3-fold higher in individuals with HPS-1 and HPS-4, and other forms of pulmonary fibrosis compared to controls and that they correlate with disease severity. Our studies to define CHI3L1 receptors revealed that CHI3L1 regulates cellular injury and repair responses in various cell types via multiple receptors or co-receptors, including IL-13R?2 (and its co-receptor TMEM219), and CRTH2 (Chemoattractant Receptor-homologous molecule expressed on Th2 cells). Our preliminary studies further highlight the importance of the CHI3L1 axis as a major contributor to the augmented fibroproliferative repair in HPS: 1) CRTH2-positive Type II innate lymphoid cells (ILC2s) are increased in the lungs of HPS mouse models of lung fibrosis; 2) the interaction of CHI3L1 with CRTH2 on these cells mediates fibroblast activation and fibroproliferation; 3) the development of fibrosis is due to defective BLOC-3 dependent trafficking of Galectin-3 (Gal-3) in fibroblasts; and 4) intracellular accumulation of Gal-3 drives fibroproliferative repair by inhibiting fibroblast apoptosis and by increasing fibroblast proliferation and myofibroblast transformation. Thus, additional investigations of the roles of CHI3L1 and its receptors in HPS-associated lung disease are warranted. We hypothesize that CHI3L1-CRTH2 axis leads to increased ILC2 accumulation, and Gal-3 production/accumulation in fibroblasts in HPS lung disease, and that targeting the moieties in this pathway will result in effective therapies. Experiments proposed in this project will investigate CHI3L1 biology in pale ear mouse models of pulmonary fibrosis with phenotypes similar to human HPS disease. These studies will define the cellular and molecular mechanisms of CHI3L1 receptor system, and whether CHI3L1 and its receptor systems are plausible targets to treat HPS-associated lung disease. In addition, targeting this pathway may benefit patients with other forms of pulmonary fibrosis including Idiopathic Pulmonary Fibrosis (IPF).